High-sensitivity differential scanning calorimetry (DSC) has been used to study the interaction of the low water-soluble anticancer agent Paclitaxel with multilamellar (MLVs) and unilamellar (ULVs) phospholipid vesicles. Three different lipid matrices have been investigated: pure di-paimitoyl-phosphatidyl-choline (DPPC), a mixture of DPPC with 3 mol% of the polymer-lipid poly(ethylene glycol: 2000) -dipalmitoylphosphatidyl -ethanolamine (PEG:2000-DPPE) and a mixture of DPPC with 10 mol% of dipalmitoyl-phosphatidyl-glycerol (DPPG). Each lipid matrix has been investigated with a Paclitaxel concentration ranging from 0 to 5 mol%. For MLVs dispersions, irrespective of the lipid matrix, the presence of Paclitaxel from I to 3 mol% causes the down shift of both pre-(T-p) and main-phase (T-m) transition temperatures and the broadening of the thermograms. The effects are, however, more pronounced on the pre-transition. The interaction of the drug with the lipid multilamellar vesicles is reduced at 5 mol% of Paclitaxel. In ULVs containing charged lipids, i.e., DPPC/PEG:2000-DPPE and DPPC/DPPG mixtures, the presence of Paclitaxel at concentrations greater than or equal to3 mol% affects significantly the main transition endothermic scans, with the appearance of side shoulders. The results suggest that the interaction of Paclitaxel is favoured with bilayer vesicles of low radius of curvature and with those containing lipids bearing a net negative charge on the polar heads. (C) 2004 Elsevier B.V. All rights reserved.